Hypertension (HTN) is a leading cause of morbidity and mortality worldwide, contributing to cardiovascular disease, stroke, and end stage kidney disease. Manifestation of the common form of HTN in any one individual is likely dependent on a variety of genetic and environment factors, hence treatment of this easily diagnosed condition is a major challenge. Recently, our laboratory identified a novel HTN gene, STK39, from a genome-wide association of baseline blood pressure (BP) in the Old Order Amish, a genetically homogeneous founder population. We then replicated this finding in 4 other non-Amish Caucasian populations (meta-analysis combining all studies: N = 7,125, P <10-6). STK39 encodes a protein kinase more commonly known as SPAK, which interacts with WNK kinases and cation-chloride co-transporters as a part of an evolutionarily conserved signaling pathway that controls salt transport and osmotic cell volume regulation. In addition we have identified a functional variant that may influence BP by increasing STK39 expression and consequently altering renal sodium excretion. An emerging body of evidence from our group and others demonstrates that SPAK participates in a signaling pathway that activates thiazide-sensitive NaCl cotransport in the kidney. Thus, genotypes that increase STK39 expression might alter renal salt handling and the BP set point, generating a sodium avid phenotype that may be amenable to correction with thiazide diuretics. Interestingly, the STK39 genotypes associated with higher BP are also associated with lower fasting glucose, raising the possibility that STK39 genotypes might predict a subgroup of salt-sensitive hypertensives with lower risk for thiazide diuretic-induced hyperglycemia. We hypothesize that the STK39 genotypes of interest are not only associated with baseline BP, but also with specific concordant responses to salt loading and thiazide diuretics. To test these hypotheses, we plan to recruit 120 Amish subjects, divided into two groups of 60 based on genotypes associated with higher versus lower baseline BP to perform 2 interventions that specifically test renal sodium chloride handling. The interventions are a short-term intravenous NaCl loading protocol followed by a dose-dependent pharmacologic BP lowering intervention with hydrochlorothiazide, a commonly prescribed thiazide diuretic. This work will be performed by a team of young investigators with expertise in genetics, ion-transporter physiology, nephrology, pharmacokinetics/pharmacodynamics, and statistical analysis. It is anticipated that these studies will shed light on the relationship between STK39 and its likely functional effect on renal sodium chloride reabsorption, thus identifying an important mediator of the salt sensitive hypertensive phenotype. The insight gained from this work may eventually help to expand our understanding of essential HTN, allowing us to reduce its genetic heterogeneity and convert its management into cost-effective personalized medicine through the identification of diuretic-responsive genotypes. RELEVANCE: Although hypertension can be easily diagnosed and there are many pharmacologic treatments, this condition is poorly managed in many patients and a leading cause of morbidity and mortality worldwide. Because a newly identified hypertension susceptibility gene, STK39, plays a central role in renal sodium transport, we propose a pharmacogenetics study to examine the relationships between STK39 genotypes and responses to salt loading and to thiazide diuretics, hydrochlorothiazide. We hypothesize that STK39 genotypes will be associated with the outcome of both interventions and can contribute to personalized care for hypertension by predicting patients most likely to effectively control their blood pressure by adopting salt-reducing diet and taking thiazide diuretics.